1. Field of the Invention
This invention relates to the resolution of ibuprofen, in particular to separating (S)-ibuprofen from a mixture of (S)-ibuprofen and (R)-ibuprofen.
2. Description of the Field
Ibuprofen, .alpha.-methyl-4-(2-methylpropyl)benzeneacetic acid, is a well-known nonsteroidal anti-inflammatory, antipyretic, and analgesic agent described in U.S. Pat. Nos. 3,228,831 and 3,385,886 (Nicholson et al.) Ibuprofen is predominantly sold commercially as the racemic compound; however, since the (S)-ibuprofen is described as being the more active enantiomer [see, for example, U.S. Pat. No. 4,851,444 (Sunshine et al.)], development of (S)-ibuprofen is well advanced.
Numerous processes for the preparation of (S)-ibuprofen have been disclosed, most related to resolution.
The use of (S)-.alpha.-methylbenzylamine as the resolving agent has been described in the patent and non-patent literature. For example, Kaiser et al., J. Pharm. Sci., 65(2), 269-273 (1976), disclose the separation of (S)-ibuprofen from racemic ibuprofen. U.S. Pat. No. 4,209,638 (Nicholson et al.) discloses a process for increasing the proportion of the desired enantiomer from racemic arylpropionic acids (such as ibuprofen) by a partial dissolution resolution technique. U.S. Pat. No. 4,983,765 (Lukas et al.) discloses a separation process in which the reaction to a diastereomeric salt takes place in a polar solvent, and the salt is purified by several crystallizations to produce optically pure material. U.S. Pat. No. 5,015,764 (Manimaran et al.) discloses a process in which the racemic mixture is initially treated with an organic or inorganic base to form a salt solution, and the salt solution is treated with a chiral base such as (S)-.alpha.-methylbenzylamine to precipitate the less soluble diastereomeric salt from the reaction solution; and PCT Published Application No. WO 93/15040 (Ethyl Corporation) discloses an improvement to that process where an inorganic or organic salt, soluble in the salt solution of the resolution process, is added to enhance the separation.
The use of other resolving agents has also been described. U.S. Pat. No. 4,994,604 (Tung et al.) discloses the use of (S)-lysine in a preferential crystallization method for the formation of the (S)-ibuprofen (S)-lysine salt; and U.S. Pat. No. 5,332,834 (Bhattacharya et al.) discloses an improvement on that process including the racemization and recycle of the (R)-ibuprofen. Published European Patent Application No. 0529835 (Nagase & Co.) discloses the use of various optically active phenyl substituted amines, such as 2-(4-methylphenyl)-3-methylbutylamine, as resolving agents.
U.S. Pat. No. 4,246,164 (Felder et al.) discloses the use of N-methyl-D-glucamine [1-deoxy-1-(methylamino)-D-glucitol, meglumine], and U.S. Pat. Nos. 4,246,193 and 4,515,811 (Holton) disclose the use of other N-alkyl-D-glucamines, as resolving agents in the preparation of naproxen [(S)-6-methoxy .alpha.-methyl-2-naphthaleneacetic acid].
U.S. Pat. No. 4,501,727 (Armitage et al.) discloses the N-methyl-D-glucamine salt of (+)-flurbiprofen [(S)-flurbiprofen]; although it does not disclose N-methyl-D-glucamine as the resolving agent for flurbiprofen.
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.